melitten and 1-amino-1-3-dicarboxycyclopentane

To examine the effects of glutamatergic neurotransmission on amyloid processing, we stably expressed the metabotropic glutamate receptor subtype 1alpha (mGlu-R1alpha) in HEK 293 cells. Both glutamate and the selective metabotropic agonist 1-amino-1,3-cyclopentanedicarboxylic acid (ACPD) rapidly increased phosphatidylinositol (PI) turnover four- to fivefold compared with control cells that were transfected with the expression vector alone. Increased PI turnover was effectively blocked by the metabotropic antagonist alpha-methyl-4-carbophenylglycine (MCPG), indicating that heterologous expression of mGluR1alpha resulted in efficient coupling of the receptors to G protein and phospholipase C activation. Stimulation of mGluR1alpha with glutamate, quisqualate, or ACPD rapidly increased secretion of the APP ectodomain (APPs); these effects were blocked by MCPG. The metabotropic receptors were coupled to APP processing by protein kinases and by phospholipase A2 (PLA2), and melittin, a peptide that stimulates PLA2, potently increased APPs secretion. These data indicate that mGluR1alpha can be involved in the regulation of APP processing. Together with previous findings that muscarinic and serotonergic receptor subtypes can increase the secretion of the APP ectodomain, these observations support the concept that proteolytic processing of APP is under the control of several major neurotransmitters.

Topics: Amyloid beta-Protein Precursor; Benzoates; Cell Line; Cycloleucine; Enzyme Activation; Excitatory Amino Acid Antagonists; Gene Expression; Glutamic Acid; Glycine; GTP-Binding Proteins; Humans; Melitten; Phosphatidylinositols; Phospholipases A; Phospholipases A2; Protein Kinases; Quisqualic Acid; Receptors, Metabotropic Glutamate; Transfection; Type C Phospholipases

Perfusion of neither the metabotropic glutamate receptor agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD), nor arachidonic acid caused any long-term enhancement of synaptic transmission in the CA1 region of the rat hippocampal slice. However, co-perfusion of ACPD (50 microM) and arachidonic acid (10 microM) for 5 min induced a rapidly evoked and long-lasting enhancement of synaptic transmission. This enhancement persisted in the presence of D(-)-2-amino-5-phosphonopentanoic acid (40 microM) and is therefore independent of NMDA receptor activation. The potentiation was mimicked by perfusion of the phospholipase A2 activator melittin (10 micrograms/ml) for 5 or 10 min, or exogenous phospholipase A2 (1 microgram/ml) for 5 min, immediately before ACPD application. We propose a role for arachidonic acid in the induction of synaptic potentiation, possibly as a retrograde transmitter substance.

Topics: Animals; Arachidonic Acid; Cycloleucine; Electric Stimulation; GABA Antagonists; Hippocampus; In Vitro Techniques; Long-Term Potentiation; Melitten; Phospholipases A; Phospholipases A2; Picrotoxin; Rats; Receptors, Metabotropic Glutamate; Synaptic Transmission